Answer: First and foremost, there is no single “best” way to manage wearing-off in a patient with PD. When most patients with PD start therapy with levodopa, which is the standard of care for management of motor symptoms associated with PD, they experience a smooth and predictable response.⁶ However, over time, many patients begin to experience fluctuations in their symptom control, resulting in the return or worsening of PD symptoms before their next scheduled dose of levodopa.⁷ For some patients wearing-off can begin as early as 1 to 2 years after initiation of levodopa therapy. Because PD affects each patient differently, it is not possible to predict when or if patients will experience wearing-off.

The symptoms of wearing-off can also vary considerably. Some patients may notice bradykinesia or tremor shortly before they are scheduled to take their next dose. Others may experience painful dystonia in various parts of the body, particularly the neck, jaw, trunk, eyes, and feet.

This diminution of levodopa’s effect is thought to be the result of increasing degeneration of dopamine terminals, so that the concentration of dopamine in the basal ganglia is much more dependent upon plasma levodopa levels. Plasma levels may fluctuate erratically because of the 90-minute half-life of levodopa and the frequently unpredictable intestinal absorption of this medication.

The risk of developing motor complications, including wearing-off, is now known to increase with higher doses of levodopa.⁸ STRIDE-PD is a prospective, double-blind international study of 745 levodopa-naïve patients with PD. This analysis compared initiation of levodopa/carbidopa with and without entacapone to determine the effect of levodopa dose and other risk factors on the development of wearing-off. Wearing-off assessments were done at 3-month intervals after initiation of levodopa treatment; patients were followed for either 134 or 208 weeks.

Patients were stratified according to nominal levodopa dose at the onset of wearing-off or at the end of the study, if no wearing-off occurred: group 1 (n = 180), levodopa <400 mg/day; group 2 (n = 325), 400 mg/day; group 3 (n = 189), >400-600 mg/day; group 4 (n = 51), >600 mg/day. Overall, the rate of wearing-off increased with dose (P =.001), with the highest rate (72.6%) seen in the highest dose group. At <400 mg/day, 27.2% experienced wearing-off; at 400 mg/day 48%, and at >400-600 mg/day 59.3%. Wearing-off was less frequent with levodopa/carbidopa/entacapone than levodopa/carbidopa treatment (P =.068).

Other factors that were predictive of wearing-off included younger age at onset of PD (P <.001), higher Unified Parkinson’s Disease Rate Scale (UPDRS) part II score at baseline (P <.001), North American over European region (P <.001), being female (P =.003), and higher UPDRS part III score at baseline (P =.046) (Table). Others studies have associated wearing-off with duration of levodopa therapy: 50%-80% of patients who receive levodopa for 5 to 10 years have motor complications.⁹

Early identification of wearing-off is important. While traditional management strategies have tended to treat the symptoms of wearing-off only when they become severe enough to interfere with daily living, recent clinical experience suggests that the earlier identification of symptoms and initiation of earlier combination therapy may allow use of lower doses of levodopa, and prolong the usefulness of this important drug.¹⁰

Dopamine agonists such as bromocriptine, pramipexole, ropinirole, rotigotine, and apomorphine are commonly used to reduce the amount of "off" time in patients with PD and may also allow for the dose of levodopa to be reduced.^11-13

COMT inhibitors may prolong and potentiate the levodopa effect and reduce the "off" time when given with a dose of levodopa.^14-16 The net result is an increased levodopa effect in patients who are experiencing fluctuations. These medications may allow a reduction in the total daily levodopa dose by as much as 30%.

Other strategies can be implemented to help mitigate wearing-off and improve quality of life in patients with PD. Levodopa is poorly absorbed, so taking multiple small doses on an empty stomach may help maintain a consistent level of dopamine. Crushing the pills and mixing them with liquid may also be helpful; a liquid formulation of carbidopa/levodopa may produce fewer fluctuations and a prolonged "on" time compared with the tablet. Prolonged-release formulations may also help control fluctuations.

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Answer: There is no proven treatment to modify disease progression in PD, so the goal of treatment is to minimize disability and maintain quality of life. In the early stages of PD, many patients can achieve good control of motor symptoms with pharmacologic therapy. The transition from early to advanced disease is often marked by wearing-off, in which patients experience motor fluctuations or nonmotor symptoms before their next scheduled dose of medication. “On-off” fluctuations, in which symptoms occur suddenly and unpredictably with no obvious relationship to medication timing, are another hallmark of advanced PD. During these sudden fluctuations, patients may experience episodic freezing and become suddenly immobilized for seconds to minutes at a time. Finally, the onset of dyskinesia is associated with advanced PD.

At this point in the disease continuum, maintaining prolonged symptom-free periods can become very challenging. Patients who are experiencing wearing-off may respond to shorter intervals between levodopa doses.¹⁷ For patients experiencing unpredictable “on-off” fluctuations, it is important to ensure that patients are not constipated and that food is not interfering with absorption of levodopa. Other preparations such as dispersible levodopa preparations, or gastrojejunostomy infusion of levodopa¹⁸ may help overcome some of the pharmacokinetic problems of levodopa absorption. Gastrojejunostomy infusion uses the same agent that has been proven effective, delivered via continuous infusion through the duodenum. This approach may satisfy the goal of bypassing the need for frequent levodopa dosing while providing continuous dopaminergic stimulation.

Addition of a long-acting dopamine agonist, such as the rotigotine patch or ropinirole can also be helpful. The PREFER study showed a more than a 30% reduction in "off" time with the rotigotine 8-mg or 12-mg patch compared with placebo.¹⁹ The main side effects observed in this particular study were somnolence, nausea and vomiting, dizziness, and dyskinesias. In the PREPARED study, patients who received the prolonged-release formulation of ropinirole showed a more than 20% reduction in "off" time compared with patients using the immediate-release formulation.²⁰ The main side effects were nausea, dyskinesia, and dizziness. The prolonged-release formulation group was able to decrease the amount of levodopa that they were using by 162 mg compared with 113 mg in the immediate-release group. Another study compared immediate-release pramipexole versus extended-release pramipexole versus placebo.¹³ Patients taking either immediate or extended-release pramipexole showed a decrease in the UPDRS II and III versus placebo. There was also a decrease in the amount of "off" time for the patients in the pramipexole group.

The addition of a COMT inhibitor to existing therapy has provided some benefit for a subset of patients.¹⁷ COMT inhibitors extend the life of levodopa, extending the life of dopamine and increasing the duration of “on” time. Entacapone and tolcapone are the available agents; tolcapone may be more potent than entacapone but requires monitoring of liver enzymes. It is important to remember that these therapies raise the level of levodopa and may increase the risk of dyskinesia and other motor fluctuations. Therefore, the dosage of levodopa may need to be reduced when adding a COMT inhibitor.

MAO-B inhibitors such as selegiline and rasagiline are also recommended to reduce “off” time. Safinamide is a MAO-B inhibitor currently under investigation. A study with safinamide 50 mg/day or 100 mg/day versus placebo showed an increase in total daily “on” time with safinamide, as well as improvement in UPDRS scores versus placebo.²¹ Results of a phase 3 study were recently presented at the 63rd Annual Meeting of the American Academy of Neurology (AAN). Over the 2-year treatment period, safinamide in addition to levodopa and other dopaminergic agents improved the time with no or minor dyskinesias. Safinamide also improved nominal motor fluctuations, parkinsonism, activities of daily living, depressive symptoms, and quality of life without worsening dyskinesia.²²

The dopamine agonist apomorphine administered subcutaneously can be used for rapid-onset rescue therapy of “off” fluctuations. In a randomized, double-blind, placebo-controlled study of 29 patients with advanced PD and ≥2 hours of "off" time despite aggressive oral therapy, administration of subcutaneous apomorphine (2 to 10 mg) resulted in successful amelioration of "off" state events following 95% of injections compared with 23% receiving placebo injection.^23,24 The drug lasts for about an hour, so patients need to continue taking their other medications.

Strategies to manage high-dose dyskinesia, which occurs at the peak effect of levodopa, include lowering the dopamine load, or reducing or discontinuing the MAO-B and COMT. Amantadine, an N-methyl-d-aspartate receptor antagonist, has also been shown to be effective.²⁵ Low-dose dyskinesia is characterized by dystonia, which often affects one or both feet. Long-acting dopamine agonists may help alleviate these symptoms. Focal dystonia may respond to botulinum toxin injections.²⁶

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